The use of substituted steroids for a number of therapeutic purposes, e.g., in the control of conception in female mammals in the regulation of the menstrual cycle, in conjunction with chemotherapy, and for a number of other purposes, has been known for some time. See, for example, G. Pincus et al., Science 124:890 (1956); J. Rock et al., Science 124:891 (1956); G. Pincus, The Control of Fertility, (New York: Academic Press, 1965); and C. Djerassi, Science 151:3716 (1966).
The present invention is specifically directed to novel progestins, i.e., synthetic progesterone-like compounds which have no natural counterpart in the human body. These compounds find a wide range of beneficial applications in human therapy. Such applications include, for example, in addition to suppressing ovulation in the human female, control of uterine bleeding, treatment of amenorrhea and dysmenorrhea, alleviation of endocrine disorders, and treatment of infertility. Examples of progestins and progestogens (i.e., naturally occurring progesterone-like compounds) which have been used for these purposes include but are not limited to acetoxypregnenolone, anagestone acetate, chlormadinone acetate, desogestrol, dimethisterone, ethisterone, ethynodiol diacetate, fluorogestone acetate, gestodene, hydroxymethylprogesterone and derivatives thereof (e.g., hydroxymethylprogesteroneacetate), hydroxyprogesteroneand derivatives thereof (e.g., hydroxyprogesterone acetate and hydroxy-progesterone caproate), levonorgestrel, lynestenol, melengestrol acetate, norethindrone, norethindrone acetate, norgesterol, normethisterone, pregnenolone, and progesterone.
Insofar as contraceptive methods and compositions are concerned, progestins are components of both the sequential and combination "pill" as well as long-acting injectables. Progestins are also administered together with an estrogenic component for the treatment of climacteric disturbances. See, e.g.: U.S. Pat. No. 3,836,651 to Rudel et al.; U.S. Pat. No. 3,932,635 to Segre; U.S. Pat. No. 3,969,502 to Lachnit-Fixson; and U.S. Pat. No. 4,145,416 to Lachnit-Fixson et al. (Progestins have also been used in oral contraceptive compositions that do not include an estrogenic component, as in U.S. Pat. No. 3,822,355 to Kincl et al. and in 4,066,757 to Pasquale. Indeed, such a formulation, containing norethindrone, is currently available and marketed under the tradename "Nor-Q.D." by Syntex Corporation, Palo Alto, Calif.)
While there are thus a number of progestins commercially available, with or without accompanying estrogenic compounds, there is a continuing need to improve efficacy and safety while minimizing unwanted side effects. Perhaps the most serious of these side effects is ancillary hormonal activity, i.e., androgenic, estrogenic and antiestrogenic activities as well as inhibition of adrenocortical function. The following table illustrates the androgenic, estrogenic, and antiestrogenic effects of currently available contraceptive formulations:
TABLE 1 ______________________________________ Androgenic Pill Progestin Effect ______________________________________ Ovcon-35 0.4 mg norethindrone 0.14 Brevicon/Modicon 0.5 mg norethindrone 0.17 Demulen 1/35 1 mg ethynodiol diacetate 0.21 Tri-Norinyl 0.5, 1.0, 0.5 mg 0.24 norethindrone Ortho-Novum 7/7/7 0.5, 0.75, 1 mg 0.26 norethindrone Ortho-Novum 10/11 0.5, 1 mg norethindrone 0.26 Triphasil/Tri- 0.5, 0.075, 0.12 mg 0.29 Levlen levonorgestrel Norinyl and Ortho 1 mg norethindrone 0.34 1/35 Nordette/Levlen 0.15 mg levonorgestrel 0.47 Lo/Ovral 0.30 mg norgestrel 0.47 Loestrin 1/20 1 mg norethindrone 0.52 acetate Loestrin 1/5/30 1.5 mg norethindrone 0.52 acetate Estrogenic Progestin Effect ______________________________________ Norgestrel (Ovral, Lo/Ovral, Nordette, 0.00 Tri-Levlen, Levlen) Norethindrone (1 mg) (Norinyl and Ortho- 1.00 Novum) Norethindrone acetate (1 mg) (Norlestrin) 1.52 Ethynodiol diacetate (1 mg) (Demulen and 3.44 Ovulen) Norethynodrel (2.5 mg) (Enovid) 20.80 Anti-Estrogenic Progestin Effect ______________________________________ Norethynodrel (2.5 mg) (Enovid) 0.0 Ethynodiol diacetate (1 mg) (Demulen and 1.0 Ovulen) Norethindrone (1 mg) (Norinyl and Ortho- 2.5 Novum) Norgestrel (0.5 mg) (Ovral) 18.5 Norethindrone acetate (1 mg) (Norlestrin) 25.0 ______________________________________
(In Table 1, androgenic activity is expressed in terms of milligrams of methyl testosterone equivalents per 28 days based on a rat ventral prostate assay. The estrogenic effect values derive from a comparative potency test based on a rat vaginal epithelium assay. See R. C. Jones et al., "The Effects of Various Steroids on Vaginal Histology in the Rat," in Fertil. Steril. 24:284 (1973). See also R. P. Dickey, Managing Contraceptive Pill Patients, 4th Ed., Durant, Oklahoma: Creative Informatics, 1984.) The values for anti-estrogenic effect are calculated using the method of R. P. Dickey as set out in Managing Contraceptive Pill Patients, 4th ed., Turant, Oklahoma; Creative information, Inc. (1984).
The ancillary hormonal activity of the above formulations is believed to be at least in part dose-related. Thus, it would be desirable to provide a novel progestin which has potent progestational activity with a minimum of ancillary hormonal activity.